Psoriasis is a common chronic debilitating disease of the skin, nails and joints with a major impact on the quality of life to levels comparable to those seen in cancer, diabetes and heart disease. Psoriasis is now recognized as a complex genetic disorder caused by the interaction of specific genetic components and the environment. Our knowledge of these factors has greatly accelerated over the last several years with the identification of genetic loci involved in immune and epidermal function. This includes risk variants within the gene encoding for the IL23 receptor (IL-23R) that have been shown to influence not only the risk of psoriasis but also other chronic inflammatory diseases such as ankylosing spondylitis and Crohn's disease. The ligand for the IL-23 receptor, which is composed of the IL-23R and the IL-12R21 chains, is Il-23, which has been shown to have a major pathogenic role in number of inflammatory and autoimmune diseases through its effect on interleukin-17 (Th17) and interleukin-22 (Th22) producing T-cells. The biological effects of the risk variants in the IL-23R are unknown but they lead to amino-acid changes in the cytoplasmic domain of the receptor and are therefore likely to change downstream signaling. The hypothesis of this proposal is that the risk variants within the IL-23 receptor increase the activity of the receptor with resulting changes in the activity of Th17 and Th22 cells. To address this hypothesis, ex vivo and in vitro studies will be performed to address the following Specific Aims: 1) To determine whether the IL23R risk variants influence mRNA, protein and surface expression of the IL-23R in vitro and in vivo. 2) Determine whether the IL23R risk haplotype exerts an influence on IL-23R signaling in T-cells c) To determine whether the IL23R risk haplotype leads to differences in Th17 and Th22 differentiation, expansion and/or function. Successful completion of these studies should increase our understanding of the physiological and pathological role of the common variants within the interleukin-23 receptor and provide new insights into the mechanisms of diseases where these variants play a pathogenic role.